Ideally, inflammation occurs as a local response to cellular injury; however, deleterious effects to the host manifest when this inflammatory response becomes systemic. Such a systemic response can occur in the setting of infection and is termed sepsis. Approximately 900,000 cases of sepsis occur annually in the United States, causing some 210,000 deaths and costing nearly $17 billion. Unfortunately, after antimicrobial therapy and supportive care is initiated, there are few therapeutic options available to these patients. However, A2A adenosine receptor (A2A AR) agonists have powerful anti-inflammatory properties and can increase survival in murine sepsis models. Currently, the pathophysiology of sepsis is not fully described and the mechanism of action of A2A AR agonists is not completely delineated. Therefore, the goals of this research application serve to further elucidate the pathophysiology of sepsis and not only to describe the beneficial effects of A2A AR agonists during sepsis, but also to discover the effects of these compounds at a cellular and molecular level. Specifically, the proposed research will address three aims: AIM1 will characterize the roles of IL-10, nitric oxide synthase, and nitric oxide in the beneficial survival effects of A2A AR agonists during murine endotoxemia and septic shock; AIM 2 will identify the molecular pathways that underpin the clinical manifestations of sepsis including identification of up- or down-regulation of toll-like receptors and down-stream signaling phospho-proteins with and without an A2A AR agonist. The role of IL-10 in this regulation will also be examined; AIM 3 will investigate the role of hematopoietic cells in the control of A2A AR agonist effects through the use of chimeric knock-out mice where the A2A ARs appear on only selected cells. This technique will be focused on one sepsis paradigm, i.e., endotoxemia. These aims are proposed to identify crucial components in sepsis pathophysiology and characterize what is potentially a useful tool in the therapeutic arsenal used to combat sepsis. [unreadable] [unreadable] [unreadable]